Neurons in the rostral portion of the ventromedial medulla (RVM) inhibit nociception in animal models of pain and play a key role in mediation of opiate analgesia. In addition, though, it has been shown that spinally projecting neurons in the RVM can facilitate nociception. Descending facilitatory neurons may mediate hyperalgesia due to inflammation; allodynia associated with neuropathic pain and may underlie aspects of opiate tolerance. However, the neurotransmitters and circuits by which descending facilitation occurs are not known. Spinally projecting neurons expressing glutamate and cholecystokinin (CCK), 2 excitatory neurotransmitters, have been reported in the RVM; Spinal glutamate receptors and CCK receptors have been reported to facilitate nociception. Thus, we propose in this application that RVM neurons expressing glutamate and/or CCK directly excite spinal nociceptive neurons. The Specific Aims of this application test corollaries of that proposition using a combination of tract-tracing, immunocytochemistry, in situ hybridization, and in vivo electrophysiology. In Aims 1 and 2 we propose to test whether RVM neurons containing glutamate and/or CCK innervate the spinal dorsal horn, including marginal zone and spinothalamic tract (STT) neurons. In Aim 3, we propose to test whether spinal cord marginal zone neurons, STT neurons and primary afferent neurons express receptors for CCK. Aim 4 proposes to test whether nociceptive neurons in rats are excited by CCK; Aim 5 proposes to determine whether spinal CCK antagonists reduce the nociceptive facilitation of spinal neurons evoked by stimulation of the RVM. Testing these hypotheses will clarify the role of spinally projecting glutamatergic and CCK RVM neurons in descending facilitation and may suggest strategies by which pain and opiate tolerance can be reduced.